Pathways to Improving Functional Capacity in Older Patients With Chronic Kidney Disease and Cardiovascular Disease

Patients with chronic kidney disease (CKD) have a high morbidity and mortality from
cardiovascular disease (CVD). Both conditions are common in older patients. Reduced exercise
capacity predicts poorer outcomes in patients with CVD2 and CKD. Although exercise tolerance
is impaired in CKD4 limited improvement in these patients is possible. A critical gap in
knowledge is how to optimize exercise capacity in these patients to improve quality and
possibly length of life.

In CKD, both structure and function of skeletal muscle are deranged. In addition, energy
production by mitochondria which falls with age, and various diseases is also reduced in CKD.
Recent studies from our group have reported that differences in mitochondrial function are
associated with variances in physical ability, exercise capacity, and gait speed.

In preliminary data, patients entering our Cardiac Rehabilitation (CR) with Stage III CKD
[glomerular filtration rate (GFR) of <60 ml/min/1.73 m2] had a decreased improvement in
exercise capacity compared to those with a normal GFR (Δ1.7 vs 2.7 Metabolic Equivalents of
Exercise or METs, p<0.05) despite the same degree of adherence. Exercise capacity after CR in
patients with a reduced GFR was greater in n-3 polyunsaturated fatty acids (n-3 PUFA) users
than in non-users [Δ MET 2.0 (1.4-2.5) vs 1.4 (1.1-1.7), p<0.05], suggesting that n-3 PUFA
with exercise may be better than exercise alone. With beneficial clinical effects in CKD, n-3
PUFA are now being extensively investigated in the dialysis population. In other patient
populations, including those with chronic obstructive pulmonary disease and dilated
cardiomyopathy daily ingestion/use of n-3 polyunsaturated fatty acids (n-3 PUFA) or fish oil
improves exercise capacity. This intervention is safe, simple and well-tolerated. Multiple
lines of evidence suggest muscle and mitochondrial function improve with exercise and n-3
PUFA supplementation.Such treatment may improve mitochondrial bioenergetics by various
mechanisms including up-regulation of mitochondrial biogenesis and genes involved in
mitochondrial fatty acid oxidation, as well as increase in mitochondrial content, and
function. Flow mediated vasodilation is impaired in CKD. It too may be improved by n-3 PUFA
supplementation which could be an alternative mechanism for improved oxygen delivery to
muscle in older patients with CAD and CKD as in the non-CKD population. A further possible
benefit of n-3 PUFA is suppression of inflammation.

Current practice, however, is to enter patients with CAD and CKD into standard CR without
prescription of n-3 PUFA.

Experimental and epidemiological studies indicate that acidemia and metabolic acidosis are
associated with the development and progression of CKD and with increased mortality in these
patients. Metabolic acidosis associated with CKD also contributes to skeletal muscle atrophy
by activation of the ubiquitin-proteasome axis. Even slight correction of acidosis can
improve the anabolic state of muscle by downregulation of the ubiquitin-proteasome system.
Clinically, bicarbonate supplementation may improve muscle function. This intervention is
also safe, simple and well-tolerated.

Given that muscular function is abnormal in CKD and that both n-3 PUFA and bicarbonate
supplementation have been shown to improve muscular function and exercise capacity, it is our
purpose in this investigation to study the effects of these substances on exercise capacity
in patients with CAD and CKD.

The investigators propose a double-blind, placebo-controlled, randomized, 2x2 factorial
design, pilot study of n-3 PUFA and/or oral bicarbonate use in older (age >60 years) CAD
patients with concomitant CKD enrolling in a standard, 3-month CR program. The investigators
will assess the effects of this intervention on exercise capacity, markers of inflammation
and serum bicarbonate concentration. The investigator's goal is to obtain 8 evaluable
patients per group. Exercise capacity will be measured by Oxygen (VO2) peak. Response to
bicarbonate will be monitored by serum bicarbonate concentration. Since CKD may adversely
affect muscle function both by acidosis and/or mitochondrial function, the investigator's
propose that these may be mechanisms for the poorer exercise capacity in these patients. The
investigator's overarching hypothesis is that exercise capacity response to CR in older
patients with CKD may be modifiable by concomitant n-3 PUFA and/or bicarbonate use to
suppress acidosis.

Inclusion Criteria:

- Referred to Cardiac Rehabilitation after acute coronary syndromes or percutaneous
intervention

- Stage III Chronic kidney disease

- Clinically stable with no mobility conditions that preclude safe walking and able to
walk

- No contraindications that will prevent measurement of physical ability and exercise
capacity including severe arthritis or musculoskeletal disorders

- knee/hip replacement or spinal surgery in past year

- Approved for participation by Principal Investigator

- Not involved in any other research study or undergoing physical therapy

- Able to provide own transportation to study visits and intervention

- Willing to provide written consent

Exclusion Criteria:

- Currently taking fish oil supplements

- Advanced malignancy or other medical condition with life expectancy less than 2 years
or undergoing active chemotherapy or radiation therapy

- Oxygen-dependent chronic obstructive pulmonary disease

- Normal kidney function or advanced chronic kidney disease (glomerular filtration rate
< 20 mL/min/1.73 m2, on dialysis or dialysis anticipated within 6 months)

- Mini-mental state examination score of ≤ 21 or previously diagnosed dementia or
cognitive impairment limiting ability to participate in rehabilitation and follow
study protocols

- Chronic anemia with hemoglobin <10 gm/dl for males, <9 gm/dl for females or acute
anemia requiring transfusion

- Significant impairment from a prior stroke or other neurologic disease or injury that
would preclude participation

- Severe peripheral arterial disease that is the primary limitation to ambulation

- Medical condition that would limit exercise

- High risk for non-adherence as determined by screening evaluation

- Patients who have undergone renal transplantation

- Currently taking bicarbonate supplementation

- Current or recent (within the last 3 months) participation in an exercise program

- Carbon Dioxide level greater than the middle of the normal range i.e. 27mmol/L and
thus predisposing to metabolic alkalosis

- Moderate 2+ or greater lower extremity edema

- Active congestive heart failure

- Ejection fraction less than 35%

- Patients using walkers and canes